Exocytosis, the process by which a vesicle fuses with the plasma membrane, is crucial to many aspects of the development and function of neurons. Exocytosis is required for the release of neurotransmitters and neuromodulators, for the insertion of receptors and channels, and for the outgrowth of axons and dendrites. Exocytosis is thus relevant both to functional disorders of the nervous system and to developmental pathologies. Little is known, however, about the extent to which the forms of exocytosis share a common machinery and the extent to which they have been specialized for their individual purposes. 1 example of such specialization can be found in a comparison of the release of neuropeptides from dense-cored granules and the release of glutamate from small, clear vesicles. These forms of exocytosis differ in their kinetics and in the forms of stimuli that most efficiently evoke release. The molecular basis of these distinctions remains unknown. In the present proposal, we use Drosophila genetics to probe the mechanism of exocytosis in both neuronal and non-neuronal cells to obtain a better understanding of this crucial cell biological process. The proposal has 2 aims. The first is to investigate the functions of the exocyst complex, 8 proteins that are required for some, but not all forms of exocytosis. We seek a better understanding of which trafficking events are dependent on the exocyst. We also propose a mutant screen to identify genes that interact closely with sec5, an exocyst component. In the second aim, we focus on 1 process for which the involvement of the exocyst remains to be determined: the release of neuropeptides at nerve terminals. We develop assays for their release and then use those assays to determine whether the exocyst required for peptide secretion.